DESCRIPTION (Applicant's Abstract): Focal regions of disorganized cortical lamination and abnormal neuronal cytoarchitecture (focal cortical dysplasia, FCD) are in utero developmental brain malformations which have been identified in many neuropsychiatric disorders including mental retardation syndromes (MR), autism, and epilepsy. FCD likely results from abnormal neural migration during corticogenesis although the molecular events leading to aberrant cortical lamination in these divergent conditions are unknown. The major difficulty in addressing the molecular pathogenesis of FCD is that many epilepsy and mental retardation syndromes are of unclear inheritance pattern rendering a genetic or pedigree analysis complicated. Thus, novel strategies must be implemented to address two compelling questions regarding the pathogenesis of FCD: 1) what is the phenotype of dysplastic cells and 2) what mechanisms are responsible for disorganized cortical lamination during corticogenesis. Answers to these questions will shed light on the practical question of how altered laminar and cellular cytoarchitecture in FCD contributes to the neurological manifestations such as seizures, MR, and behavioral abnormalities in such a wide variety of neurological disorders. Three sets of experiments will investigate the phenotype of dysplastic cells in human FCD specimens and assess the expression of developmentally regulated genes necessary for cortical lamination in an experimental model of FCD. Because of the heterogeneous cell types within FCD, a central feature of the proposed experiments is the use of single cell mRNA amplification technology. This novel approach permits quantification of mRNA abundance in individual immunolabeled or live neurons that are of similar or distinct phenotype. Analysis of human FCD specimens will provide a direct avenue to investigate the developmental phenotype of FCD neurons. The model FCD system will permit assessment of gene regulation during the dynamic phases of cortical migration. The overall objective of the proposal is to determine the molecular pathways that lead to disorganized cortical cytoarchitecture in FCD. Furthermore, by identifying altered expression of select genes, the relationship between FCD and various mental disorders can be discerned. These analyses may point toward new avenues for therapy.